Criscuolo Chiara, Chartampila Elissavet, Ginsberg Stephen D, Scharfman Helen E
Center for Dementia Research, the Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, 10962, USA.
Department of Child & Adolescent Psychiatry, New York University Grossman School of Medicine, New York, NY, 10016, USA.
bioRxiv. 2023 May 8:2023.05.07.539742. doi: 10.1101/2023.05.07.539742.
The neurotrophin brain-derived neurotrophic factor (BDNF) is important in development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated Alzheimer's disease (AD) because hippocampal levels in AD patients and AD animal models are consistently downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus (DG) granule cells (GCs), has been understudied, and never in controlled conditions. We examined MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild type (WT) mice of both sexes were examined at 2-3 months of age, when amyloid-β (Aβ) is present in neurons but plaques are absent, and 11-20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either genotype or sex. Notably, we found a correlation between MF BDNF protein and GC ΔFosB, a transcription factor that increases after 1-2 weeks of elevated neuronal activity. Remarkably, there was relatively little evidence of Aβ in GCs or the GC layer even at old ages. Results indicate MF BDNF is stable in the Tg2576 mouse, and MF BDNF may remain unchanged due to increased GC neuronal activity, since BDNF expression is well known to be activity-dependent. The resistance of GCs to long-term Aβ accumulation provides an opportunity to understand how to protect other vulnerable neurons from increased Aβ levels and therefore has translational implications.
神经营养因子脑源性神经营养因子（BDNF）在神经元的发育、维持及其可塑性方面起着重要作用。海马体中的BDNF与阿尔茨海默病（AD）有关，因为AD患者和AD动物模型中的海马体水平一直下调，这表明BDNF减少会导致AD。然而，海马体BDNF蛋白表达最高的部位，即齿状回（DG）颗粒细胞（GCs）的苔藓纤维（MF）轴突，尚未得到充分研究，且从未在受控条件下进行过研究。我们在AD的Tg2576小鼠模型中检测了MF BDNF蛋白。对2至3个月大（此时神经元中存在淀粉样β蛋白（Aβ）但不存在斑块）以及11至20个月大（斑块积累后）的Tg2576和野生型（WT）雌雄小鼠进行了检测。如先前所示，WT小鼠表现出高水平的MF BDNF蛋白。有趣的是，无论基因型或性别，其水平均未随年龄显著下降。值得注意的是，我们发现MF BDNF蛋白与GC ΔFosB之间存在相关性，GC ΔFosB是一种在神经元活动增强1至2周后增加的转录因子。值得注意的是，即使在老年时，在GCs或GC层中也相对很少有Aβ的证据。结果表明，MF BDNF在Tg2576小鼠中是稳定的，并且由于GC神经元活动增加，MF BDNF可能保持不变，因为众所周知BDNF的表达是依赖于活动的。GCs对长期Aβ积累的抗性为了解如何保护其他易损神经元免受Aβ水平升高的影响提供了机会，因此具有转化意义。
